Epidemiological and clinical risk factors related to severe COVID-19 in Iran: a multi-center study

Background Iran was one of the first countries to be affected by COVID-19. Identifying factors associated with the severity of COVID-19 is effective in disease management. This study investigated the epidemiological and clinical features and factors related to the severity of COVID-19 in one of the less privileged areas in Iran. Methods In a multi-center study, all patients admitted to Zahedan University of Medical Sciences hospitals in southeastern Iran were investigated from February 29 to April 31, 2020. Demographic, epidemiological, and clinical data of patients were extracted from medical records. Bivariate and multivariate logistic regression models were used to explore the risk factors associated with the severity of COVID-19. Results Among the 413 patients, 55.5% were male, and 145 (35.10%) were in a severe condition at admission time. Multivariate analysis showed that the adjusted odds of the disease severity increased in patients with older age (OR 2.27; 95% CI 1.41–3.65), substance abuse (OR 2.49; 95% CI 1.14–5.43), having one underlying disease (OR 1.52; 95% CI 0.90–2.55), having two underlying disease (OR 2.31; 95% CI 1.19–4.50), and having three or more underlying disease (OR 2.60; 95% CI 1.19–5.66). Conclusions COVID-19 was more severe in older patients, patients with a history of substance abuse, and patients with the underlying disease. Understanding the factors affecting the disease severity can help the clinical management of COVID-19, especially in less privileged areas where fewer resources are available.

Iran occurred [3]. However, there is no comprehensive report regarding risk factors related to severe COVID-19 disease in Iran.
There is evidence that hypertension, respiratory disease, cardiovascular disease increase the risk of severe COVID-19 [8][9][10], and men are at higher risk [11]. However, it seems that health records are often incomplete or inaccurate [12], and it is expected that the severity pattern of COVID-19 and its risk factors will change soon. Morbidity to severe COVID-19 will increase the risk of death and consequently impose more expense on the health system. Therefore, it gives the impression that the estimation of risk factors for severe COVID-19 could be helpful for physicians to manage the patient treatment and effectively prioritize resources for patients with the highest risk [13], especially in deprived regions. Evidence shows that individuals with lower socioeconomic status during the COVID-19 pandemic may be more vulnerable and neglected, possibly because of disease burden, poor health literacy and access to healthcare [14]. Social factors that either lead to barriers to timely access to care or create a situation in which patients consider the delay in care the most reasonable option influence the disparities in outcomes between COVID-19 patients [15].
To our knowledge, no previous report has been published from patients with severe conditions and their characteristics in less privileged areas of Iran. Sistan and Baluchistan province is located in the southeast of Iran and has common borders with Pakistan and Afghanistan. This province has the lowest position in the development indices of the provinces of Iran. Zahedan is the capital of Sistan and Baluchestan province [16]. It is hypothesized that the characteristics and risk factors for COVID-19 are different in this area. Therefore, we aimed to determine the potential risk factors of severe COVID-19 patients and describe patients' epidemiological and clinical characteristics during hospitalization. As the first study of this region, the results could also provide the basis for comparison in future epidemiological studies.

Study design and population
This study was carried out on 413 COVID-19 patients in all hospitals affiliated with Zahedan University of Medical Sciences, southeast of Iran. All patients diagnosed with COVID-19 according to WHO interim guidance [17] between February 29 , 2020, and April 31, 2020, were included in the study. These hospitals were referral for the transfer of patients with COVID-19 from other medical centers in Zahedan. Therefore, the current study considered all adult inpatients hospitalized for COVID-19 during the mentioned time.

Evaluation of clinical results
According to the WHO clinical management of COVID-19 guideline, symptomatic patients without evidence of viral pneumonia or hypoxia were classified as a mild disease. Patients with clinical signs of pneumonia but no signs of severe pneumonia were grouped as a moderate disease. Patients with oxygen support were classified as a severe disease, and those with further complications were classified as a critically ill disease [17].

Data collection
Epidemiological and demographic characteristics and clinical data (symptoms, underlying disease, treatments, complications after admission, and outcomes) were extracted from medical records. In addition, the complementary data were collected by interviews with patients or their companions through two well-informed infectious disease residents and one anesthesia resident during hospitalization and referring to health centers during the early stage of the disease. Exposure history was defined as exposure to people with confirmed COVID-19 infection. Special and sub-special physicians approved all clinical data, symptoms, and signs based on standard definitions. Two researchers checked all data.
COVID-19 detection in respiratory specimens by RT-PCR methods was supervised by the center for disease control and prevention at the ministry of health in Iran. At the commence of the epidemic, the throat-swab specimens obtained from COVID-19 suspects were sent to the reference laboratory at Tehran University of Medical Sciences (school of public health) and Pasteur Institute of Iran. From March 11 , 2020, the specimens were examined in a laboratory launching for COVID-19 detection in Zahedan city. The throat-swab samples were obtained from patients with fever, cough, and dyspnea symptoms. A confirmed case was defined as a suspected case with a positive test of RT-PCR assay on respiratory specimens.

Statistical analysis
The absolute frequency and percent were used to describe the categorical variables. The mean and standard deviation was used to summarize continuous variables. Differences between severe and non-severe patients regarding epidemiological and clinical factors and underlying diseases were compared using independent samples t-test, chi-square test, Fisher's exact test. Bivariate and multivariate logistic regression models were used to explore the risk factors associated with disease severity. The logistic regression was chosen for multivariate analysis based on previous findings and clinical constraints considering the collinearity before fitting the model. We excluded variables from the bivariate analysis if their between-group differences were not significant, accuracy was unconfirmed, and the number of events was too small to calculate odds ratios. The data were analyzed in Stata. 16, and the significance level was considered as 0.05.

Results
Of 413 patients admitted to hospitals, 55.5% were male, 38.5% had aged more than 50. The mean age of the patients was 45.05 ± 17.38, ranging from 10 to 92 years. Regarding epidemiological characteristics, 9% and 3.9% of patients reported drug use and cigarette smoking, respectively. Patients who traveled to high-risk areas within 14 days before the onset of symptoms were 13.6%. Close contact with a respiratory patient in a medical center, family, and workplace was 5.9%, 9.2%, and 2.7%, respectively. About 4% of patients reported a history of close contact with a COVID19 patient within 14 days before the onset of symptoms. Among patients, 41.4% used mask protection, and 54.7% personally went to a medical center. At admission, 145 (35.10%) patients were in severe and 268 (64.90%) non-severe conditions. There was a significant relationship between age and severity of COVID-19. The odds of severe disease were 3.38 times greater in patients aged more than 50 years, and it was 2.09 times greater in substance abuse cases. Patients referred to the hospital by ambulance (OR 3.53) were more likely to be in a severe condition of COVID-19 compared to those who went to the hospital personally. Although wearing a mask decreased the odds of severity (OR 0.38), there was no significant relationship between the mask protection and the disease severity. There were 16 (3.9%) cigarette smokers, and smoking was not the predictor of severity among COVID-19 patients (Table 1).
Regarding clinical symptoms at admission, 37% of patients had a temperature of more than 37.5. The most prevalent symptoms were cough (71.2%), breath shortness (61.2%), fever (32.2%), shiver (29%), and bruising (28.4%). An abnormal computed tomography was found in 94.5%. In univariate analysis, cough, shortness of breath, abdominal pain, lack of appetite, and loss of consciousness were related to the disease severity among COVID-19 patients. Shortness of breath increased the odds of severe COVID-19 (OR 1.93). The odds of severe COVID-19 was significantly greater in patients with abdominal pain (OR 7.7), seizure (OR 27.1), and loss of consciousness (OR 12.4) ( Table 2). Among all patients, 1.4% had a runny nose, and 1.7% had no sign.
In univariate analysis, sepsis, respiratory failure, acute respiratory distress, heart failure, acute kidney and liver injury were related to the severity of disease among COVID-19 patients. The odds of severe COVID-19 was significantly greater in patients with sepsis (OR 26.3), respiratory failure (OR 39.1), acute respiratory distress syndrome (OR 30.81), heart failure (OR 24.2), acute heart injury (OR 11.5), acute kidney injury (OR 11.7), liver injury (OR 3.7) and acidosis (OR 11.5) ( Table 2).
Among all patients, 37% had an oxygen saturation of more than 0.93, 11.4% were eventually admitted to the ICU, and 8.7% received mechanical ventilation. According to oxygen therapy, 90.6% received high flow nasal cannula (HFNC) and 8.2% invasive mechanical ventilation. The odds of severe disease increased significantly in patients admitted to ICU (OR 27.8) and mechanically ventilated patients (OR 84.9). Oxygen saturation of more than 0.93 could prevent the disease severity by 70%. The mean heart rate and respiratory rate were significantly different between the severe and non-severe patients (P < 0.001) ( Table 4). About 36 (94.7%) of the severe patients were intubated. Most patients took antibiotics (91.5%) and antiviral drugs (97.3%) but were not related to severity among COVID-19 patients (P > 0.05).
Multivariate analysis was performed on all variables found significant by univariate analysis in Tables 1, 2 and 3. Multivariate regression showed increased odds of the severity for COVID-19 was associated with older age (OR 2.27), substance abuse (OR 2.49), having one underlying disease (OR 1.52), having two underlying diseases (OR 2.31), having three or more underlying diseases (OR 2.60) ( Table 5).

Discussion
The current study investigated the clinical characteristics of patients with COVID-19 and potential risk factors for severity. Univariate analysis revealed that age, substance abuse, traveling to high-risk areas, means of transportation to a medical center, cough, shortness of breath, abdominal pain, lack of appetite, loss of consciousness,   Among the 413 patients in this study, 145 (35.10%) were in severe condition, and older patients were at higher risk of severe disease. Inadequate immune response in older patients leads to more complicated and critical conditions such as ARDS, severe clinical manifestations, and longer disease duration [18,19]. Other studies have reported a lower prevalence of disease severity, including 17.6% and 25.6% [20,21], which is expected based on various definitions.
In the current study, substance abuse was a risk factor for COVID-19 severity, resulting from direct damage to the respiratory system, modulating brain and immune functions [22]. Severe disease was also associated with travel to high-risk areas. This finding highlights the importance of social distancing on viral inocula reduction [23], leading to less severe disease [24]. Exposure to confirmed cases and recent travel to the epidemic area are the host risk factors for severe COVID-19 [25].
In terms of signs, this study showed that cough, shortness of breath, abdominal pain, losing appetite, heart rate, and the number of breathing were associated with severity in COVID-19 patients. Gastrointestinal symptoms are more prevalent in severe COVID-19 patients, so 100% of these patients experience a lack of appetite. The increased viral load and the spread of the virus in the gastrointestinal tract of COVID-19 patients can lead to the severity of the disease [26]. Other studies have shown that cough, shortness of breath, and abdominal pain are common in patients with severe COVID-19 [27][28][29]. Furthermore, high respiratory and heart rates were the risk factors for the severity in COVID-19 patients [30].
The present study showed a decreased level of consciousness, oxygen requirement at hospitalization, ICU admission, invasive mechanical ventilation, intubation, and oxygen saturation were risk factors for severity in    COVID-19 patients. Previous studies have shown that only severe patients need to be admitted to the ICU, and oxygen saturation is lower in severe patients. In addition, unconsciousness, shortness of breath, oxygen therapy, invasive and non-invasive mechanical ventilation were also more common in severe patients [31][32][33][34].
In the current study, complications during treatment, sepsis, respiratory failure, acute respiratory distress syndrome, heart failure, acute heart injury, acute kidney injury, and acidosis were risk factors for severity in COVID-19 patients. The cause of respiratory failure in patients with COVID-19 was impaired immune function [35]. Uncontrolled viral infection causes macrophage penetration and further damage to the lungs [36]. Serious complications such as acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, and shock can occur in patients with severe COVID-19. Acute respiratory distress syndrome and acute cardiac injury are the most important barriers to treating COVID-19 patients [37]. Cardiac injury is associated with the severity of disease in patients with COVID-19 [38]. The SARS-CoV-2 affects the cardiovascular system through angiotensin-converting enzyme 2 (ACE2) and causes myocardial injury and heart failure [39,40]. Acute kidney injury (AKI) is an indicator of disease severity. Volume depletion may be the cause of acute kidney injury [41]. The prevalence of liver dysfunction and liver injury is higher in patients with severe COVID-19. Liver impairment may be caused directly by a viral infection of the liver cells or by hepatotoxicity caused by drugs and immune-mediated inflammation [42].
In terms of underlying health conditions, cardiovascular disease, liver disease, chronic pulmonary disease, hypertension, and rheumatologic disease were risk factors for severe COVID-19 in this study. Underlying health conditions are responsible for 20% of severe COVID-19 worldwide [43]. Severe COVID-19 patients experience a higher incidence of comorbidity, a risk factor for the severity of COVID-19 pneumonia [44,45]. Patients with established cardiovascular disease exhibited a greater angiotensin-converting enzyme 2 (ACE2) expression and probably experienced a worse condition following SARS-CoV-2 infection [46,47]. Patients with a history of hypertension are more likely to develop severe COVID-19 as hypertension is a predictor of severe pneumonia [48,49]. There is evidence that antihypertensive drugs prevent patients with comorbid hypertension from severe pneumonia. Chronic respiratory conditions are also associated with the severity of COVID-19 [50]. Elevated liver biochemical indicators are common in COVID-19, resulting in severe COVID-19 [51,52]. Patients with rheumatic diseases are at high risk for COVID-19 infection due to their immune conditions [53]. In addition, chronic inflammatory rheumatic patients with autoimmune or immune-mediated diseases are at risk of severe COVID-19 [54].

Conclusions
COVID-19 was more severe in older patients, patients with a history of substance abuse, and patients with underlying disease. Understanding the factors affecting the disease severity can help the clinical management of COVID-19, especially in less privileged areas where fewer resources are available.
One of the strengths of the present study is that the patients were selected from a less privileged area which can draw the attention of health policymakers to this area. Another strength of the study is the multi-center nature of the survey, representing the population. This study had some limitations: First, the small sample size, leading to insignificant statistical results. Therefore, the results of this study should be interpreted with caution. Further studies are needed to investigate potential risk factors of severity in patients with COVID-19 with large sample size. Second, the information was collected as a self-report in some cases, leading to recall bias.